Tetracyclic thiophenepyrimidinone compounds as inhibitors of 17β hydroxysteroid dehydrogenase compounds

Abstract

Thiopheneprymidinone compounds useful in therapy, especially for use in the treatment and/or prevention of a steroid hormone dependent disorder, preferably a steroid hormone dependent disease or disorder requiring the inhibition of a 17β-hydroxysteroid dehydrogenase (17β-HSD) such as 17β-HSD type 1, type 2 or type 3 enzyme.

1. A method of treating a steroid hormone dependent disease or disorder, requiring the inhibition of the 17β-HSD type 1, 17β-HSD type 2 or 17β-HSD type 3 enzyme, wherein the steroid hormone dependent disease or disorder is selected from the group consisting of breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, colon cancer, endometrial cancer, endometrial hyperplasia, endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, acne, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome, urinary dysfunction and osteoporosis, said method comprising administering to a patient suffering from one or more of the aforementioned steroid hormone dependent diseases or disorders an effective amount of a compound corresponding to formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  together with their binding sites form a cyclic 5-, 6-, 7- or 8-membered ring system, which is saturated or contains one or more double bonds between the ring atoms, and wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl or arylalkyl wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, aryl-S(O) 1-2 —, alkyl-S(O) 1-2 —, hydroxyl, oxo, halogen, amino, oxime, —(C═O ) —R, —(C═O ) —O—R, thiocarboxyl, and amido; 
 R 3  and R 4  form together with their binding sites a cyclic 5-, 6-, 7- or 8-membered hydrocarbon ring system, which is saturated or contains one or more double bonds between the carbon atoms, and 
 wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl or arylalkyl wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, aryl-S(O) 1-2 —, alkyl-S(O) 1-2 —, hydroxyl, oxo, halogen, amino, oxime, —(C═O )—R, —(C═O )—O—R, thiocarboxyl, and amido; 
 wherein R may be hydrogen, alkyl, aryl, or aryl-(C 1 -C 4 )-alkyl, both optionally substituted in the aryl group 
 or a physiologically acceptable salt thereof; 
 provided that said compound is not 1,2,7,8,9,10,11,13-octahydro-13-oxo-4-(phenylthio)-[1]benzothieno[2′,3′:4,5]pyrimido[1,2-a]azepine-3-carboxaldehyde. 
 
     
     
       2. A method according to  claim 1 , wherein said compound corresponds to formula (II) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  form together with their binding sites a cyclic 5-, 6-, 7- or 8-membered ring system, 
 which is saturated or contains one or more double bonds between the ring atoms, and 
 which ring contains zero, one or two N-atoms in addition to the nitrogen atom where R 1  is attached, 
 wherein said ring is substituted with zero, one or two substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, aryl-S(O) 1-2 —, alkyl-S(O) 1-2 —, hydroxyl, oxo, halogen, amino, oxime, —(C═O )—R, —(C═O )—O—R, thiocarboxyl, and amido; 
 the hydrocarbon chain —C(R 5 )—C(R 6 )—(CH) n — of the ring-system adjacent the thiophene-ring is saturated or contains one or more double bonds between the carbon atoms; 
 n is an integer from 1 to 4, and 
 R 5  and R 6  are individually selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl or arylalkyl wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, aryl-S(O) 1-2 —, alkyl-S(O) 1-2 —, hydroxyl, oxo, halogen, amino, oxime, —(C═O )—R, —(C═O )—O—R, thiocarboxyl, and amido 
 wherein R may be hydrogen, alkyl, aryl, or aryl-(C 1 -C 4 )-alkyl, both optionally substituted in the aryl group. 
 
     
     
       3. A method of treating a steroid hormone dependent disease or disorder, requiring the inhibition of the 17β-HSD type 1, 17β-HSD type 2 or 17β-HSD type 3 enzyme, wherein the steroid hormone dependent disease or disorder is selected from the group consisting of breast cancer, prostate carcinoma, ovarian cancer, uterine cancer, colon cancer, endometrial cancer, endometrial hyperplasia, endometriosis, uterine fibroids, uterine leiomyoma, adenomyosis, dysmenorrhea, menorrhagia, metrorrhagia, prostadynia, benign prostatic hyperplasia, acne, hirsutism, androgenic alopecia, precocious puberty, adrenal hyperplasia, polycystic ovarian syndrome, urinary dysfunction and osteoporosis, said method comprising administering to a patient suffering from one or more of the aforementioned steroid hormone dependent diseases or disorders an effective amount of a compound corresponding to formula (II) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  form together with their binding sites a cyclic 7-membered ring system, which is saturated or contains one or more double bonds between the ring atoms, and which ring contains zero N-atoms in addition to the nitrogen atom where R 1  is attached; 
 wherein said ring is substituted with zero, one or two substituents independently selected from the group consisting of oxo, —CO—R, —CO—O—R, —O—R, and —C 1 -C 4 -alkyl, optionally substituted with —O—R, —S—R or —N(R) 2;    
 the hydrocarbon chain —C(R 5 )—C(R 6 )—(CH) n — of the ring-system adjacent the thiophene-ring is saturated or contains one or more double bonds between the carbon atoms; 
 n is an integer from 1 to 4; and 
 R 5  and R 6  are individually selected from the group consisting of hydrogen, oxo, halogen, —O—R′, —S—R′, —SO—R′, —CO—R, —CO—O—R, —C 1 -C 4 -alkenyl or ═C 1 -C 4 -alkylene, optionally substituted in the alkyl chain with —O—R, —S—R, —N(R) 2 , —CO—R, or ═N—O—R, wherein
 R represents hydrogen or C 1 -C 4 -alkyl; and 
 R′ represents hydrogen, C 1 -C 8 -alkyl, which can be linear, cyclic or branched; aryl-C 1 -C 4 -alkyl, or aryl.